The Janus kinase, Tyk2, plays a pivotal role in controlling the expression of genes involved in immune responses, cell transformation and maintaining homeostasis. Results in this proposal define a new function for Tyk2 as a key mediator of brown adipocyte differentiation. Mice that do not express Tyk2 become obese and have a defect in brown fat cell-specific gene expression. Furthermore, mice placed on a high fat diet and obese humans show decreased expression of Tyk2 in skeletal muscle. Differentiation of Tyk2-/- preadipocytes in vitro and in transgenic animals is rescued by the expression of Tyk2, as well as a kinase-inactive form of the enzyme that cannot be activated by cytokines. Furthermore, there is a pool of Tyk2 in the nucleus that interacts with transcription factors that are required for differentiation of brown adipose tissue (BAT). Experiments are proposed to understand the mechanisms by which expression of Tyk2 regulates BAT differentiation and prevents the development of obesity.